A Pilot Randomized Controlled Trial of Conductive COOLing of the Ischemic PENumbra in Patients With Acute Ischemic Stroke.

PEN-Cool is a pilot, multicentre, randomized controlled trial evaluating a novel non-invasive active conductive combined head-and-neck cooling system for selective brain cooling in adults with acute ischemic stroke receiving reperfusion therapy. The study is part of a phased translational research programme involving technology development, validation in healthy volunteers, and clinical evaluation in patients with acute ischemic stroke.

The clinical trial will enroll 40 adult patients with acute ischemic stroke who are eligible for intravenous thrombolysis, endovascular thrombectomy, or both. Participants will be centrally randomized in a 1:1 ratio to either adjunctive selective brain cooling plus standard reperfusion therapy or standard reperfusion therapy alone.

In the intervention group, the conductive cooling system will be applied to the scalp and anterolateral and posterolateral neck. Cooling will begin before intravenous thrombolysis and/or endovascular thrombectomy in the emergency department or angiography suite and will continue for up to 120 minutes. The cooling interface will deliver temperatures ranging from -5°C to 0°C. Brain temperature will be monitored non-invasively using infrared tympanic membrane thermometry, while core body temperature will be monitored using a rectal or esophageal probe. Blood pressure, heart rate, and oxygen saturation will also be monitored.

Cooling will be discontinued if predefined safety or tolerability criteria are met, including intolerance, persistent cold-related shivering despite passive warming, core body temperature of 35°C or below, uncontrolled hypertension, symptomatic bradycardia or other unexpected medical events, or procedural complications.

The primary feasibility outcome is adherence to the cooling intervention, defined as receiving head cooling for at least 60% of the intended total cooling duration. Secondary feasibility outcomes include interruptions in cooling and monthly enrollment rate. Efficacy outcomes include early neurological improvement, defined as a 30% or greater improvement in NIHSS score at 24 hours, and good functional outcome, defined as a modified Rankin Scale score of 0-2 at 3 months. Safety outcomes include symptomatic bradyarrhythmia, uncontrolled hypertension, cold-related shivering, cervical or cerebral vasospasm requiring intra-arterial vasodilators, symptomatic intracranial hemorrhage, pneumonia, and mortality through 3 months. Process outcomes include time from hospital arrival to initiation of cooling and time from arrival to reperfusion therapy.